Macrocyclic lactones, and in particular, the “macrolides” are naturally derived and semi-synthetic compounds with a range of biological activities. Amongst the best known of these activities is antibiotic activity through binding to the bacterial ribosome. Certain of these compounds do, however, have other activities including anti-inflammatory activity (see European patent publication 0283055). In recent years, macrocycles may have been used as drug carriers in which an active substance is reversibly bonded to the macrocycle via an ester bond (see, e.g., PCT Publication 03/070174). However, remaining antibiotic activity of the macrocycle has the attendant danger of promoting bacterial resistance to this drug class amongst the patient population.
Various observations have linked bacterial resistance to macrocycles to either mutation of the ribosome subunits, or up-regulation of efflux processes (see Douthwaite et al., J. Antimicrob. Chemother. (2001) 48 (suppl 2): 1-8, for review, and Bonnefoy, et al., J. Antimicrob. Chemother. (1997) 40 (1): 85-90). The efflux systems in a range of bacteria are considered to recognize in part the so-called “cladinose” sugar found in the erythromycin derived macrocycles. Removal of this sugar therefore means the potential of reducing the capacity for a macrocyclic compound to stimulate non-specific antibiotic resistance.
Although cladinose is part of the efflux recognition motif, there are a number of anti-bacterial molecules, the so-called ketolides, that have either no cladinose group, or a modification at the cladinose position. Thus, decladinosyl species are not intrinsically non-antibacterial and decladinosyl azithromycin is ca. 5-fold less effective than the cladinosylated molecule. However, it would desirable to provide a compound having anti-inflammatory activity and at the same time, complete or at least partial elimination of antibiotic activity, e.g., at least one hundred-fold or more less effective as antibiotics, in order to avoid imposing selection pressure for resistance.
Various workers have attempted to design such molecules. The most common approach is based on the idea of sterically blocking the site that interacts with the target bacterial ribosome. For example, the hydroxyl and amine groups on the desosamine ring are the main interactors with the ribosome and reaction at these sites with bulky groups reduces antibacterial activity. However, addition of bulky groups to this position, while facile, leads to larger molecules which are intrinsically less suitable as pharmaceuticals because their large size make them more likely to interact with non-target receptors.
A large number of researchers have reported derivatives of macrocycles (see, e.g., Elliot et al., 1998, J. Med. Chem. 41, 1651-1659); however, these derivatives have typically been limited to substitutions on the macrolactone ring or modifications of the sugar residues (cladinose to carbonyl for example in the case of the ketolides). Working on methylated macrolides, Kobrehel et al. (U.S. Pat. No. 6,369,035) reported intermediates following oxidation with ketolide-like properties as antimicrobial compounds.